Alcoholic hepatitis is an inflammatory disease of the liver that occurs for unknown reasons in a minority of chronic alcoholics. Inflammation is the underlying cause of liver injury and the cause of symptoms and death. Prednisolone, the most commonly recommend treatment, improves survival in most, but not all, patients. In particular, prednisolone does not improve survival among patients with a Lille score e0.45. To improve overall survival in alcoholic hepatitis, new treatments are needed for patients who fail to respond to prednisolone. We propose to evaluate two drugs in alcoholic hepatitis. First, we will test rilonacept, a drug directed against the pro- inflammatory cytokine, interleukin-1, in patients with a Lille score <0.45 (responders to prednisolone). Because these patients have an excellent survival with prednisolone treatment (standard of care treatment), we will determine whether the addition of rilonacept for three weeks (rilonacept+prednisolone) will result in a more rapid improvement in serum bilirubin (a measure of liver function). Second, we will test the mycophenolate, a drug directed against lymphocytes, among patients with a Lille score e0.45. Because these patients have a 25% mortality at 1 month (and 75% mortality at 6 months), the primary outcome will be a reduction in 28-day mortality among patients receiving prednisolone+mycophenolate as compared with no treatment (standard of care). Use of a prednisolone+mycophenolate is designed to markedly reduce hepatic inflammation in patients who do not respond to prednisolone. Because the combination of prednisolone+mycophenolate is a potent immunosuppressant, patients will be monitored closely for infection and all infections will be reported promptly to a Data Safety Monitoring Board. This clinical trial is a component of a large, translational research project that will investigate liver inflammation, hepatocellular injury and regeneration using immunohistology, immunologic studies of peripheral blood, liver transcriptomics, liver proteomics and a systems biology approach to data analysis. This clinical trial and the associated translational projects will lead to a better understanding of the inflammatory pathways involved and provide data for potential new treatments for alcoholic hepatitis PUBLIC HEALTH RELEVANCE: Patients who respond to prednisolone, the current treatment for severe acute alcoholic hepatitis, have a 15% mortality at 6-months. Unfortunately, 35% of patients fail to respond to prednisolone and have a 75% mortality at 6 months. The current clinical trial will investigate new treatments for alcoholic hepatitis, especially among patients wo fail to respond to prednisolone.